Multidrug resistance is a phenomenon which has been observed in cancer and in a number of parasitic diseases such as malaria, tuberculosis, Entamoeba histolytica (amoebic dysentery), Trypanosoma (African sleeping sickness), Leishmania and AIDS pneumonia.
A number of diverse drugs have been found effective against such diseases. However in many cases, the initial success of physicians in treating the disease is followed by total failure. Drugs which worked initially become totally ineffective after a period of time. An initial period of remission is often followed by a period of frustration during which nothing seems to be effective against the disease. Death becomes inevitable.
Such multidrug resistance in cancer cells has been associated with an increase in the drug resistant cell of the presence of 150,000 to 170,000 molecular weight glycoproteins. Such P150-170 Kd glycoproteins act as a drug exit pump, to pump disease fighting drugs out of the infected or infecting cells which the drugs are supposed to kill. This glycoprotein pump phenomenon in cancer cells has been reported in a March 1989 Scientific American article by Kartner and Ling. (No concession is made that this publication is prior art as to subject matter contained in the parent applications.) The presence of a very similar glycoprotein pump in drug resistant malaria has also been discovered by the inventor.
It has been reported by Rothenberg and Ling that multidrug resistance in cancer can be reversed by using hydrophobic molecules with two planar aromatic rings and a tertiary basic nitrogen atom with a positive charge at physiologic pH. Journal of the National Cancer Institute, Vol. 81, No. 12, Jun. 21, 1989, on page 907. (No concession is made that this publication is prior art as to subject matter contained in the parent applications.) A representative compound of this class, and indeed apparently a member of this class which has actually been the subject of much experimental work is the drug verapamil, whose structural formula is shown below: ##STR1##
Verapamil is a calcium channel blocker. Other researchers have claimed that calcium channel blockers are effective against malaria. However while such results may be substantiatable in vitro, they have little practical value as clinical treatments in vivo. While calcium channel blockers are therapeutic in the treatment of hypertension at moderate levels, they are toxic at levels high enough to effect MDR reversal.
Another technique for MDR reversal in cancer which is of laboratory interest but which has no practical applicability involves inducing point mutations of the energy related ATP binding sites in the glycoprotein. Such point mutations result in an almost complete loss of MDR activity, according to Rothenberg and Ling, supra. While such in vitro work is important, it lacks in vivo clinical applicability.
Shiraishi et al. disclose in vitro work on the use of cepharanthine to treat multidrug resistance in cancer. Isotetrandrine, d-tetrandrine, fangchinoline and berbamine are said to show similar effects in cancer. Anti-tumor effects of d-tetrandrine have also been mentioned.
Heretofore, the phenomenon of multidrug resistance in such disease cells has been attributed to the presence of naturally occurring P150-170 Kd glycoproteins in the disease cells. It is believed that when the disease colony is exposed to treatment, the cells with the glycoprotein, or with a higher percentage thereof, survive the initial treatment while cells without glycoprotein, or with a lesser concentration thereof, do not. The surviving remnant then reproduces and eventually creates a colony which is substantially if not totally resistant to treatment with any drug.
A recent publication in the Proceedings of the National Academy of Science, reveals that multidrug resistance can also be caused by viral infection. "A retrovirus carrying an MDR1 cDNA confers multidrug resistance and polarized expression of P-glycoprotein in MDCK cells," Proc. Natl. Acad. Sci. USA, Ira Pastan et al., Vol. 85, pages 4486-4490, June 1988, Medical Sciences. The authors inserted a full-length cDNA for the human multidrug resistance gene (MDR1) into a retroviral vector. They were able to infect cells with this virus so that the cell expressed P-glycoprotein and rendered the cell multidrug resistant.
This experimental work raises the specter of multidrug resistant infection through accidental release of such manufactured retrovirus. Perhaps more significantly, it suggests the possible natural occurrence of retrovirus carrying such cDNA.
The implications of these possibilities are that diseases normally treatable with drugs initially, including cancers, may become untreatable ab initio due to infection with such multidrug resistance carrying virus. Such virus could through natural or artificial means infect body cells which may later become cancerous, or could infect the cells of parasitic diseases such as malaria, tuberculosis, AIDS pneumonia, African sleeping sickness and other such diseases. The presence of sizable colonies of such multidrug resistant disease cells would render the diseases and cancers particularly aggressive and virulent and very possibly baffling to an unsuspecting physician.
Researchers throughout the world continue to press for techniques for reversing multidrug resistance. A successful clinical technique for reversing multidrug resistance will be one of the most important breakthroughs in the fight against cancer, malaria, tuberculosis and other diseases exhibiting the multidrug resistance phenomenon.